Faculty Bibliography

Study question: Does NGS for PGS improve pregnancy outcomes as compared to array comparative genomic hybridization (aCGH)? Summary answer: NGS improves implantation and ongoing pregnancy rates/live birth rates compared to aCGH among patients undergoing in vitro fertilization (IVF) with PGS. What is known already: Array CGH is widely used for IVF with PGS. NGS, a new platform for PGS, may be able to detect more cases of mosaicism and triploidy (69XXY) than aCGH. Genetic abnormalities detected by NGS are significantly higher among pregnancies resulting in miscarriage than live birth. Study design, size, duration: This was a retrospective study of 1015 patients undergoing IVF with PGS followed by single thawed euploid embryo transfer (STEET) from 1/2014 to 12/2016 at a single university medical center. Participants/materials, setting, methods: All IVF cycles with PGS and STEET were included. Oocyte thaws for biopsy, double embryo transfers (ET), mosaic ET, or cycles with incomplete outcome data were excluded. Primary outcomes: implantation rate (IR), spontaneous abortion rate (SABR), and ongoing pregnancy rate/live birth rate (OPR/LBR). Demographic data included age, gravidity, parity, number of prior IVF cycles, ovarian reserve testing, and infertility diagnosis. Student's t-test and Fisher's exact test were used for statistical analysis with P < 0.05 considered significant. Main results and the role of chance: 424 patients underwent PGS with aCGH, and 591 patients underwent PGS with NGS. 18 patients were excluded from the NGS group for incomplete outcome data (11) or mosaic ET (7). There was no difference in baseline demographics between groups. The mean age of patients was 35.7 years. IR was significantly higher in the NGS group compared to the aCGH group (71.7% vs. 65.1%, p = 0.027). The OPR/LBR was also significantly higher in the NGS group (62.3% vs. 55.0%, p = 0.023). The SABR was decreased in the NGS group compared to the aCGH group, but this was not statistically significant (11.9% vs. 12.7%., p = 0.813). Limitations, reasons for caution: This study was limited by its retrospective design. Prospective data on the outcomes of mosaic embryo transfers is needed to determine their true implantation potential. Wider implications of the findings: PGS using NGS significantly improves pregnancy outcomes over PGS using aCGH. Mosaic embryos may have reduced implantation potential. Therefore, the exclusion of mosaic embryos with NGS may explain these results

The ovaries have a fixed pool of immature (primordial) follicles at birth known as the ovarian reserve. Activation or loss of follicles in this reserve causes an irreversible decline in reproductive function that culminates in menopause. Premenopausal women with cancer who are treated with conventional genotoxic chemotherapy have accelerated loss of the ovarian reserve, leading to subfertility and infertility. Cyclophosphamide (CY), a highly gonadotoxic drug, is widely used as part of combination cancer chemotherapy. This drug induces ovarian damage in large part by activating the mammalian/mechanistic target of rapamycin (mTOR) pathway, leading to activation of primordial follicles, follicular burnout, and premature menopause. As a result, the probability of pregnancy in premenopausal female cancer survivors is significantly diminished. There has been little progress in preserving ovarian function during cancer chemotherapy. As part of multiagent chemotherapeutic regimens, inhibitors of themTORC1 pathway have a growing role in cancer treatment and are being studied as treatment for a growing number of malignant and nonmalignant conditions. Mammalian/mechanistic target of rapamycin inhibitors block the primordial-to-primary follicle transition. The investigators used a clinically relevant mouse model of chemotherapy-induced gonadotoxicity to investigate whether inhibitors of mTOR could block CY-induced premature activation of primordial follicles and also preserve fertility during chemotherapy. Two inhibitors of the mTOR pathway were used: everolimus (RAD001), a drug clinically approved for treatment of tamoxifen-resistant or relapsing estrogen receptor-positive breast cancer), and INK128, an experimental drug. Female mice were treated with CY weekly and then randomized to also receive either everolimus, INK128, or nothing.